Age-related macular degeneration (AMD) is the leading cause of irreversible central visual loss in the aged population in the world. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation causes a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-control individuals with normal retinas. Up to date, 419 individuals have been enrolled and 60 histopathological cases with AMD have been collected. We also received and analyzed 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from a historical NEI project of AREDS. We are comparing the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects followed by the functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we have identified genetic risk factors of AMD and the possible roles of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above approches, a genetically engineered animal has been generated to act as the AMD model. In FY2009, we have accomplished the following: (1) established a sophisticated data mining platform for large scale data analysis;(2) completed the study on Htra1, TLR3 and TLR4 SNP-AMD association and published two papers in Ophthalmology and IOVS;(3) Completed the the study of the interation of Chlamydia infection and AMD SNPs and published the result in BJO;(4)further characterized the retinal lesions in Ccl2/Cx3cr1 double knock-out (DKO) mice - a murine model of AMD, and reported the involvement of Htra2/Omi in the retina lesion of the model;(4) Added the experiments on the test of long-chain omega-3 fatty acid on the retinal lesions of the DKO mice and published the paper in AJP, (5) started to test various compounds and gene therapy in vitro and in vivo (DKO) models;(6) creared 7 Material Transfer Agreetments (MTA), and 1 Collaborative Research and Development Agreement(CRADA) for researchers other than NIH and pharmaceutical company to use our DKO model for mechanistic and therapeutic purposes.